Integrin-binding Peptide for Ocular Neovascularization and Macular Edema: Molecular Mechanism of Action

整合素结合肽治疗眼部新生血管和黄斑水肿：分子作用机制

基本信息

批准号：
10361561
负责人：
Peter A Campochiaro
金额：
$ 39.71万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-01 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10361561
关键词：
Address Advanced Development Agonist Angiogenesis Inhibitors Angiogenic Peptides Angiopoietin-2 Angiostatins Binding Biomimetics Blindness Blood Vessels Cell Proliferation Characteristics Cicatrix Collagen Type IV Complex Data Disease Disease Progression Dissociation Dose Doxycycline Drug Kinetics Endostatins Endothelial Cells Extravasation Exudative age-related macular degeneration Eye Family Gel Goals Human Injections Insulin-Like-Growth Factor I Receptor Integrin Binding Intercellular Junctions KDR gene Maintenance Malignant neoplasm of brain Malignant neoplasm of lung Medical Methods Migration Assay Modeling Molecular Molecular Mechanisms of Action Mus Opsin Oryctolagus cuniculus Oxygen Patients Penetration Peptides Permeability Phosphorylation Photoreceptors Physiological Platelet-Derived Growth Factor beta Receptor Process Production Property Proteins Receptor Signaling Retina Retinal Diseases Retinal Vein Occlusion Sampling Series Signal Transduction Structure Systems Biology Testing Tetanus Helper Peptide Therapeutic Therapeutic Agents Time Tissues Transgenic Mice Transgenic Organisms Translating Vascular Diseases Vascular Endothelial Growth Factor Receptor-1 Vascular Endothelial Growth Factors Visual Wild Type Mouse antagonist aqueous diabetic dimer disability experimental study in vivo inducible gene expression macular edema malignant breast neoplasm monomer mouse model multicatalytic endopeptidase complex neovascularization novel therapeutics ocular neovascularization peptidomimetics prevent receptor response retina blood vessel structure rho wound healing

项目摘要

Project Summary Endogenous protein inhibitors of neovascularization (NV) and vascular leakage have great potential as therapeutic agents for retinal and choroidal vascular diseases, but thus far that potential has not been realized partly because large proteins present challenges for manufacturing, maintenance of appropriate folding, and penetration into tissues. We have developed a collagen IV-derived 20-mer peptide mimetic, AXT107 that strongly suppresses ocular neovascularization and vascular leakage. Intravitreous injection of 1µg of AXT107 in mice has comparable activity to 40µg of aflibercept and when combined, activity is greater than with either alone. In rabbit eyes, 50µg AXT107 suppresses vascular leakage longer than 500µg aflibercept because it self-assembles into a gel depot in the vitreous cavity that provides sustained delivery to the retina. The goal of this proposal is to elucidate the mechanism of action of AXT107 and the mechanism by which it self-assembles into a gel depot which provides prolonged activity. Preliminary data show that AXT107 binds αvβ3 which disrupts signaling through VEGFR2. AXT107 also disrupts signaling through platelet-derived growth factor receptor β (PDGFRβ), c-Met, and insulin-like growth factor-1 receptor; we will test the hypothesis that these effects are also a consequence of αvβ3 binding. AXT107 binds α5β1 and activates Tie2 in the presence of Angiopoietin 2 (Angpt2). We will test the hypothesis that AXT107 binding dissociates α5β1 into monomers, thereby eliminating α5β1-induced constraint of Tie2 allowing it to translocate to cell junctions and form multimers that are activated by Angpt2 increasing junctional integrity. In mice with oxygen-induced ischemic retinopathy (OIR), we will test the hypothesis that high levels of Angpt2 which reduce the effects of the VEGF antagonist aflibercept, enhance the antiangiogenic and anti-permeability effects of AXT107 because in its presence Angpt2 is converted from a Tie2 antagonist to a Tie2 agonist. We will also test the hypothesis that AXT107 is superior to aflibercept + anti-Angpt2 because it does not depend solely on endogenous Angpt1 for Tie2 activation. The mechanism of AXT107 assembly and disassembly, and its effect on pharmacokinetics will be investigated. These studies will advance the development of AXT107 a novel therapeutic that combines two important activities, VEGF suppression and Tie2 activation, with prolonged duration of action, and thus addresses unmet medical needs for retinal and choroidal vascular diseases.

项目摘要内源性蛋白质蛋白抑制剂（NV）和血管泄漏具有很大的潜力视网膜和脉络膜血管疾病的治疗剂，但到目前为止尚未实现潜力部分是因为大型蛋白质提出了制造的挑战，维持适当的折叠以及渗透到组织中。我们已经开发了一个胶原蛋白IV衍生的20-Mer肽模拟物，AXT107 强烈抑制椭圆形的新血管形成和血管泄漏。静脉注射1µg AXT107 在小鼠中，活性与40µg的Aflibercept相当独自的。在兔子眼中，50µg AXT107抑制血管泄漏长于500µg aflibercept 自组装成玻璃体腔中的凝胶仓库，可持续向视网膜递送。目标该建议是阐明AXT107的作用机理及其自组成的机制进入提供长时间活性的凝胶仓库。初步数据表明，AXT107结合了αVβ3 通过VEGFR2破坏信号。 AXT107还通过血小板来源的生长因子破坏信号传导受体β（PDGFRβ），C-MET和胰岛素样生长因子1受体；我们将检验以下假设作用也是αVβ3结合的结果。 AXT107结合α5β1并在存在下激活TIE2 Angiopietin 2（Angpt2）。我们将测试AXT107结合将α5β1分解为单体的假设，从而消除了TIE2的α5β1诱导的约束，使其可以转移到细胞连接和形成由Angpt2激活的多中rirrs增加了连接完整性。在具有氧诱导缺血的小鼠中视网膜病变（OIR），我们将测试以下假设：高水平的Angpt2降低了VEGF的影响拮抗剂Aflibercept，增强了AXT107的抗血管生成和抗渗透性作用存在Angpt2从TIE2拮抗剂转换为TIE2激动剂。我们还将检验以下假设 AXT107优于Aflibercept + Anti-ty-tempt2，因为它不仅取决于内源性angpt1 TIE2激活。 AXT107组装和拆卸的机制及其对药代动力学的影响将被调查。这些研究将推动AXT107的发展，一种新的疗法，结合了两个重要的活动，VEGF抑制和TIE2激活，延长的作用持续时间，因此解决残留和脉络膜血管疾病的未满足医疗需求。